| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Research Abstract |
Although vascular endothelial growth factor (VEGF) plays a role in growth of hypervascular tumors, mechanisms for paracrine regulation of its receptor expression on vascular endothelial cells remain unknown. This study aimed to investigate whether VEGF released from hypoxia-exposed HepG2 cells alter expression of two distinct receptors, KDR and fit-1, *n human umbilical venous endothelial cells (HUVECs). HepG2 cells Were cultured in 20% 02 or 1% 02 for 16 hours in order to examine induction of VEGF mRNA and its protein expression. Conditioned media of HepG2 cells (CM) were applied to HUVECs under normoxic conditions, and expression of mRNA for the VEGE receptors was determined by RT-PCR.In response to the hypoxic challenge, HepG2 cells upregulated VEGF mRNA and the release of VEGE.The hypoxia-CM stimulated preferentially the mRNA expression of fit-1, but not that of KOR in HUVECs. When the VEGF release from hypoxia-exposed HepG2 cells was blocked by its antisense-oligodeoxynucleotide,
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the endothelial fit-1 mRNA upregulation elicited by the hypoxia-CM was still maintained. These results suggest that hypoxia-exposed hepatic cancer cells can not only produce VEGF but also evolve paracrine induction of fit-1 through VEGE-independent mechanisms.
Transcatheter hepatic arterial embolization (TAE) therapy is one of the hypoxic challenge to hepatocellular carcinoma (HGC). Therefore, we examined the level of VEGE in sera of patients with HCC who underwent TAE during the course of the treatment. Methods. Thirty eight patients with HCC and hepatitis C virus-positive cirrhosis were studied. Peripheral blood samples were taken before and 1, 3 7 days after TAE with informed consent. The serum levels of VEGF as well as hepatocyte growth factor (HGF), another hepatic remodeling factor, were measured. The molar ratio (BTR) of serum branched chain amino acid (BCAA) to tyrosine (Tyr), the serum levels of AST, ALT and LDH were also examined. Results. Although the level of AST, ALT and LDH *ched to the peak value within 1 day after TAE, VEGF increased significantly 7 days later. On the other hand, there were no significant alterations in the levels of HGF and BTR during the course of TAE.Although the level of HGF was significantly correlated with the level of VEGF before TAE, no remarkable correlation was observed after TAE.These data collectively suggest that VEGF may be secreted in response to clinical hypoxic intervention, TAE, independent of HGF or the condition of amino acid metabolism. VEGF may play a role as a sensitive marker for hepatic tumor ischemia. Less
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